2-(n-piperidino-methyl)-indanes, their salts and preparation thereof



Patented Aug. 23, 1949 2,479,744 2- (N-PKPERIDINO METHYL) JNDANES,

'rnsm w THEREOF SALTS AN D PREPARATION Karl Hoiimann and Henri Schellenberg, Basel,

and Karl Miescher, Riehen, Switzerland, assignors to Ciba Pharmaceutical Products Inc.,

Summit, N. J., a firm Application March 10, 1945, Serial No Drawing.

No. 582,188. In Switzerland January 4', 19Mv 7 Claims.

in application Serial *No. 535,740, filed May 15, 1944, new U. S. Patent No. 2,441,069, granted May 4, 1948, is described a process for the manufacture of amines which consists in subjecting indane compounds which contain in the five-membered ring an amino-alkyl group and as further substituent a free or substituted hydroxyl group, to a treatment which eliminates the latter substituent together with the hydrogen atom attached to a neighboring carbon atom with the formation of a double bond, and, if desired, converting these amines into their ammonium compounds. The aminoalkyl-indenes thus obtained are characterized in particular by their uterotonic activity. It has now been found that corresponding compounds saturated in the five-membered ring are, surprisingly, just as valuable uterotonics.

The present invention relates to a process for the manufacture of amines which consists in treating indane compounds which contain in 2'- position of the fivenembered ring an aminoalkyl group substituted at the nitrogen atom and as a further nuclear grouping a keto group, a free or substituted carbinol group or an alkylene group, with reducing agents to remove the oxygen or saturate the unsaturated group, and, if desired, causing agents which form quaternary compounds to act on the resulting products.

The starting materials can further be substituted in one or both rings and contain a secondary or tertiary amino group. With regard to the starting materials which can be used, reference is made inter alia to the above mentioned speci- ,fication.

Agents which are suitable for removing oxygen from the compounds containing carbonyl groups are described for example in Houben, Die 'lviethoden der organischen Chemie, 3rd edition, v01. 2, pages 276-279. Accordingly, when starting from indanones which contain in the fivemembered ring an aminoalkyl group, for example catalytically activated hydrogen, further also phosphorus and hydriodic acid or amalgamated zinc and hydrochloric acid can be used as reducing agents. The catalytic reduction can be carried out in the presence of noble catalysts, such as platinum, palladium or if desired on a catalyst carrier. It is preferable to work in anhydrous iatty acids, such as glacial acetic acid or propienic acid, and also in the presence of mineral acids, such as sulfuric acid, hydrochloric acid, perchloric acid, zinc chloride-hydrochloric acid, or, e. g., of boron fluoride-acetic acid. If necessary, the reduction is performed at a raised temperature and/or under increased pressure. Ii

the aminoketones used as starting materials are little stable in the "free state, it is advantageous to start from their salts and work in an acid or neutral solution. The corresponding compounds which contain in the five-membered ring instead of the keto group a free or substituted, particularly esterified carbinol group or an alkylene group, can be, reduced in analogous manner. Moreover, also catalytic reduction in the presence of base catalysts, such as e. g. nickel or nickelcobalt, is suitablefor the reduction of an alkylene group. Suitable solvents are for example alcohol, dioxane, water, etc.

The 2-aminoalkyl-indanes obtained in this way generally distil off undecomposed, are stable and yield water-soluble salts which crystallize well, If desired, they. can be converted into the corresponding ammonium compounds according to known methods.

The new compounds find application in therapy or as intermediate products for the manufacture of compounds for therapeutic application.

The following examples illustrate the invention, but are not to be regarded as limiting it in any way, the parts being by weight:

hydrochloride of melting point 227-228 C. of the formula 1 (prepared, e. g., from u-indanone by condensation with paraformaldehyde and piperidine hydrochloride, reduction of the resulting 1-oxo-2- (N-piperidino-methyl)-indane-hydrochloride of melting point 214 C. with sodium amalgam to the corresponding l-hydroxy compound of melting point 2065-207? C. and subsequent elimination of water) aredissolved in 50 parts of absolute alcohol and the acid solution is neutralized with about 30 parts of l-N caustic soda solution. 15 parts of previously reduced nickel catalyst are added to the solution and the whole is shaken with hydrogen at room temperature. The hydrogenation ceases practically after 1 mol of hydrogen has been absorbed. The filtered reaction solutionls evaporated and the residue distilled. It boils at 1l0-112 C. under 0.35 mm.

pressure. The Z-(N-piperidino-methyl)-indane thus obtained of the formula,

reducing l hydroxy-z- (N-piperidino-methyl) -inane or a correspondingacylo'xy-derivative such as the acetoxy- 'or benzoyloxy derivative with hydrogen- 1hthe'presence 'of, e. g., palladiumbarium sulfate c'atalyst' and "sulfuric acid in a glacial. acetic acid'solution. a

The 2 (dimethylaniino-methyl) indane, the

hydrochloride o f- ;which nielts' t 189-190" 0. or *the 2-(N-morpholino methyl)-indane are obtained in analogous manner.

7 Example 2 2 parts of concentrated hydrochloric acid are added to a solution'='of- 10.6 parts of l-oxo-z-(N- piperidino-methyl)-indane-hydrochloride of the formula (prepared; e; g; as indicated in Example 1) in 200 parts of glacial acetic acid and the whole is shaken with 0.2 part of platinum oxide at about.

60 C. in an atmosphere ofhydrogen. After the quantity of hydrogen calculatedifor 2 mols has been absorbed, themixtureis' allowed to cool, the filtered reactioniselution is evaporated and the base is liberated from the crystallized residue with caustic soda solution. For the purpose of purification the precipitated .oil is taken up in ether, the ethereal solution isis'haken with 2n-hydrochloric acid, the hydrochloric extract is alkalized with ammonia andthebase is again taken up in ether. The residue of theethereal. solution is distilled in a high' vacuum. 7 The main fraction which passes over at 96-98" C. under 0.1 mm. pressure proves 1 to be identical with the Z-(N- piperidino-methyl)-indane obtained according toEXample 1. H

When using 1-oxo 2-(methylaminomethyl) -indame-hydrochloride or melting point l58.-l59 C (prepared according to'the aforesaid application) as starting materiaLthere is obtained Z-(methylamino-methyl) -indane in analogous manner,

, which'forms a hydrochloride of melting point 4 Example 3 If the reaction is conducted in an analogous manner as in Example 1 but with use of 1-methyl- 2- (N-piperidino-methyl).-indene of the formula there is obtained the l-methyl-Z- (N-piperidinomethyl-Z-(Npiperidino-methyl)- indane of the formula CHa as an oil which forms a crystalline water-soluble hydrochloride.

In a quite similar-manner there are obtained other derivatives substituted in the 5-membered ring and/ or in the aromatic nucleus, particularly ior example i-ethyl-, 1-.propyl-,- 1-is0propyl-, 1- butyl-, l-phenyl-, l benzyl-indane derivatives, which contain in the 2-position an amino-methyl group substituted at-the nitrogen atom.

The ring numbering in the indane compounds in the present specificationis inaccordance with the scheme:

What we claiin is: 1. A process for the. manufacture of an ami which comprises treating an indane compound 7 which contains an N-piperidino-methyl group in the 2-positi0n of the five-membered ring and a member selected from the class consist ng of a keto group, a carbinol group, a substituted carbfnol group and an allrylene group in the l-position of ,the'five'membered ring, with hydrogen in the ,presehce'of acatalyst selected from the group consisting ofplatinum and palladium at atmospheric pressure and at a temperature not ,substantially'in' excess of 6., whereby the reduction takes place without affecting the degree of m saturationof the six-membered carbon ring" of; platinum at atmospheric pressure a aii'ectingjthe degree of unsaturation of the H which comprises treating l-rhydrozrs flfli A dine-methyl) -indane:with hydrogen in the pic.)

of the indane compound. 2. A process for the'nianufactureor" a which comprises treating '2-(I T- nzethyD-indene with hydrogen in tit temperature, whereby the fit-eonembered s ne of the said indene is saturated without, her

melnbered carbon ring thereof, so that the 2 (i.

piperidino methyli-indane is produced.

3. A process for thernianuiacture of amine,

ence of platinum and of mineral acid at atmospheric pressure and atroom temperature, whereby the five-membered ringof the said indane is freed from oxygen and is saturated without, however, affecting thedegree of-unsaturation of the six-membered carbon 'ring' thereof, so that the -2 (N-piperidinoemethyl)-indane is produced.

. 4. A process'forthe manufacture of an amine, which comprises treatingrl-oxo-2-N-piperidinow methyl) -indane with hydrogen in the presence of platinum and of mineral acid at atmospheric pressure and at about 60 0., whereby the fivemembered ring of the said indane is freed from oxygen and is saturated without, however, affect ing the degree of unsaturaticn of the six-membered carbon ring thereof, so that the 2-(N- piperidino-methyl)indane is produced.

5. A member selected from the group consisting of the indane compounds which are saturated in the five-membered ring and contain in the 2-position an N-piperidino-methyl group, the nitrogen atom of which is connected to the said five-membered ring through the methyl group, and their salts and ammonium compounds.

6. The Z-(N-piperidino-methyl) -indane of the formula 7. The hydrochloride of Z-(N-piperidinomethyl) -indane, having a melting point of about 220-221 C.

KARL HOFFMANN. HENRI SCHELLENBERG. KARL MIESCHER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,175,003 Sly Oct. 3, 1939 2,265,174 Kendall Dec. 9, 1941 FOREIGN PATENTS Number Country Date 395,232 Great Britain July 13, 1933 OTHER REFERENCES Patterson et al., Ring Index (Rheinhold Pub. Co., New York, 1940), page 134.

Fieser et a1., Organic Chemistry (D. C. Heath 8; Co, Boston, 1944), page 543.

Beilstein, Handbuch etc., vol. 5, First Sup- :0 plement, p. 234; vol. 5, Second Supplement, p. 411.

Certificate of Correction Patent No. 2,47 9,744 August 23, 1949 KARL HOFFMANN ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 4, line 13, efterthe Word methyl first occurrence, strike out -2-(N- piperidino-methyl and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 27th day of December, A. D. 1949.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

